title: Sequence heterogeneity of NS5A and core proteins of hepatitis C virus and virological responses to pegylated-interferon/ribavirin combination therapy.
abstract: Both host and viral factors have been implicated in influencing the response to pegylated-interferon/ribavirin (PEG-IFN/RBV) therapy for hepatitis C virus (HCV) infection. Among the viral factors, sequence heterogeneity within NS5A and core regions has been proposed. This study aimed to clarify the relationship between virological responses to PEG-IFN/RBV therapy and sequence heterogeneity within NS5A, including the IFN/RBV resistance-determining region (IRRDR), the interferon sensitivity-determining region (ISDR) and the core region. Pretreatment sequences of NS5A and the core regions were analyzed in 57 HCV-1b-infected patients who were to be treated with PEG-IFN/RBV. Of 40 patients infected with HCV having an IRRDR with four or more mutations (IRRDR ≥ 4), 28 (70%) patients achieved a sustained virological response (SVR). On the other hand, only 4 (24%) of 17 patients infected with HCV having an IRRDR with three or fewer mutations (IRRDR ≤ 3) achieved a SVR (P = 0.001). Similarly, 22 (71%) of 31 patients infected with HCV and having an ISDR with one or more mutations (ISDR ≥ 1) achieved a SVR while 10 (38%) of 26 patients infected with HCV and having an ISDR without any mutations (ISDR = 0) achieved a SVR (P = 0.014). As for the core region, there was significant correlation between a single mutation at position 70 (Gln(70) ) and non-SVR (P = 0.02). Notably, Gln(70) was more prominently associated with the null response (P = 0.0007). In conclusion, sequence heterogeneity within the IRRDR and ISDR, and a single point mutation at position 70 of the core region of HCV-1b are likely to be correlated with virological responses to PEG-IFN/RBV therapy.
authors.affiliation: Division of Microbiology, Center for Infectious Diseases, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Ahmed
authors.initials: A
authors.lastname: El-Shamy
authors.forename: Ikuo
authors.initials: I
authors.lastname: Shoji
authors.forename: Takafumi
authors.initials: T
authors.lastname: Saito
authors.forename: Hisayoshi
authors.initials: H
authors.lastname: Watanabe
authors.forename: Yoshi-Hiro
authors.initials: YH
authors.lastname: Ide
authors.forename: Lin
authors.initials: L
authors.lastname: Deng
authors.forename: Sumio
authors.initials: S
authors.lastname: Kawata
authors.forename: Hak
authors.initials: H
authors.lastname: Hotta
mesh_terms: D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000008:administration & dosage / Q000494:pharmacology; D004359:Drug Therapy, Combination / Q000379:methods; D005260:Female; D014644:Genetic Variation; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics; D006526:Hepatitis C / Q000188:drug therapy / Q000821:virology*; D006801:Humans; D007372:Interferons / Q000008:administration & dosage* / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D012367:RNA, Viral / Q000097:blood / Q000235:genetics; D012254:Ribavirin / Q000008:administration & dosage* / Q000494:pharmacology; D017422:Sequence Analysis, DNA; D016896:Treatment Outcome; D014758:Viral Core Proteins / Q000235:genetics*; D019562:Viral Load; D017361:Viral Nonstructural Proteins / Q000235:genetics*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D007372:Interferons; D012367:RNA, Viral; D012254:Ribavirin; D014758:Viral Core Proteins; D017361:Viral Nonstructural Proteins; C069130:nucleocapsid protein, Hepatitis C virus; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase